alpha, alpha-difluoro-substituted acids of the tricarboxylic acid cycle, their salts, amides and esters



United States Patent a,a-DIFLUOR0-SUBSTITUTED ACIDS OF THE TRI- CARBOXYLIC ACID CYCLE, THEIR SALTS, AMIDES AND ESTERS Maynard S. Raasch, Wilmington, DeL, assignor to E. I. du Pont de Nemours and Company, Wilmington, Dei., a corporation of Delaware No Drawing. Application September 20, 1955 Serial No. 535,538

7 Claims. (Cl. 260-483) This invention relates to a new class of organic compounds containing fiuorine and to their preparation. More particularly this invention relates to new fluorine-containing carboxylic acids, their salts, amides and esters and methods for their preparation.

The tricarboxglic acid cycle, also known as the Krebs or citric acid cycle, is a key biochemical process that occurs in most living organisms and is involved in the oxidative metabolism of carbohydrates. Pyruvic acid from carbohydrate metabolism is fed into the cycle and by means of it is oxidized to carbon dioxide and water with the release of energy. Some of the compounds in the cycle also function as intermediates for other biochemical processes. The series of enzymic reactions represented by the cycle occurs in the mitochondria of cells and can be represented as follows (see Fruton and Simmonds General Biochemistry, John Wiley and Sons, Inc., New York 1953, p. 471):

TRICARB OXYLIC ACID CYCLE CHaC O O 0 OH pyruvic acid -2H CO2 +COA CHaC O-GOA (CoA=Coenzyme A) HOCIIHOOOH 2H OCCOOH HZCCOOH HaCCOOH HsCCOOH HOCCOOH H20 0 0 OH malic oxalacettc citric acid acid acid I-l-Hzo l-HRO HO O O OH HO O 0 FR 0 C 0 0H HCCOOH HQCOOOH fumaric aconitic acid acid L-ZH I'd-H2O I 0([7COOH CO OCIJCOOH HOCHCOOH mocoon w HM) no coon HCCOOH HzCOOH a raccoon moooon raccoon succinic 2-0xogluoxaloisocitric acid taric acid 5110915110 acid aci Certain analogs and derivatives of the acids in the cycle are known to be inhibitors of the cycle. Thus, malonic acid inhibits the dehydrogenation of succinic acid by interfering with the succinic dehydrogenase enzyme (Fruton and Simmonds, p. 472). Inhibition of the cycle has become of economic importance in the control of pests. Fluoroacetic acid is believed to be toxic because it is metabolized to fluorocitric acid which then blocks the cycle at the citric acid stage (Fruton and Simmonds,

p. 476). However, fluoroacetic acid is extremely toxic to mammals, including humans, and therefore dangerous to use. As an index of this toxicity, the LD (dosage lethal to 50% of the animals tested) for the sodium salt of fluoroacetic acid to laboratory white mice (intraperitoneal route) is only about 9-l0 mg./ kg. body weight.

It is an object of this invention to provide a new class of organic compounds containing fluorine and methods for their preparation. A further object is to provide new fluorine-containing carboxylic acids, their salts, amides and esters and methods for their preparation. A still further object is to provide a new class of fluorinesubstituted derivatives of acids in the tricarboxylic acid cycle. Another object is to provide a new class of fluorinecontaining compounds showing fungicidal, insecticidal and miticidal activity with a relatively low toxicity to mammals. Other objects will appear hereinafter.

These and other objects of this invention are accomplished by providing a,a-difluoro-substituted acids of the tricarboxylic acid cycle, their salts, amides and esters. Each member of this new class of a,a difluoro-substituted acids is derived from an acid of the tricarboxylic acid cycle having a methylene group by replacing with fluorine the hydrogens of the methylene group. These acids are otherwise unsubstituted. Thus, these new fluorinecontaining acids correspond in chemical structure to the acids of the tricarboxylic acid cycle having a methylene carbon atom alpha to a carboxyl group and have directly attached to this methylene carbon atom two fluorine atoms. Although fumaric acid is an acid of the tricarboxylic acid cycle, it does not contain a methylene carbon atom and hence cannot have an a,a-difluoro-substituted acid derivative.

The new a,a-difiuoro-substituted acids of this invention consist of the following eight acids:

(2) 0:,a-DifiHOIOCltIiC acid (alternatively named 2,2- difluorocitric acid) (3) a,a-Difluoroaconitic acid (alternatively named 4,4- difiuoroaconitic acid) (4) m,a-Difiuoroisocitric acid (alternatively named 4,4- difluoroisocitric acid) (6) a,a-Difiuoro-gamma-oxoglutaric acid (alternative ly named 4,4-difluoro-2-oxoglutaric acid) (7) 0:,a-DlfiI1OI'OSHCClHiC acid (alternatively named 2,2-difluorosuccinic acid) (8) a,a-Difluoromalic acid (alternatively named 3,3- difluoromalic acid) HO O C-CH-C Fr-C O OH The members of this new class of a,udifluoro acids show fungicidal, insecticidal and miticidal activity, yet

I have a relatively low toxicity to mammals.

It appears probable that the insecticidal and fungicidal activity which is characteristic of this classof compounds may hea manifestation of th'eir interference with the normal :operation of the tricarboxylic acid cycle, and that their greatly reduced toxicity to mammals over the known monofluoro derivatives 'is'due to the presence of a difluoroliiethylene group alpha to a carboxyl group. This theory. is given for a better, understanding of the nature and properties of the :novel compounds of this invention and obviously in no manner is to be considered as a limitation on the scope of the present invention.

Thfifigct-dlflllol'o derivatives of the acids in the triciarboxylic acid cycle are illustrated in the following examples iii-which partsare by weight. I

'iExiyr nple I.-.+ qz,ot-'diflu oroxizlacetic acid V In a glassreaction vessel, fitted with stirrer, thermometer, .inlet for liquid addition, and heater are. placed 830 parts of diethyl 'oxalate and .69 parts of finely divided sodium hydride, --The assembly is flushed with nitrogen and then 353 parts of ethyl difluoroacetate is added dur-' ing'three'hours at 75-80 C. Heating is continued for five 'hours longer; 'The. cooled mixture is added to, 294 parts of-sulfu'ric aciddissolved in 1500 parts 'of water; The organic layer is. separated and the aqueous layer is extracted with ether. The organic layer and ether extract are combined and dried with magnesium sulfate and thendistilled. The yield of diethyl 1a,oz-difluor0oxalacetate is '244'parts (38% oftheol'y), B. P. 63 'C./.1"

du-ce gentle reflux. tinued for one hour.

to give 39 parts of theory) of triethyl 2,2-difluorocitrate, B. P. 1251 26.5 C./.1 mm., n -1.4215

Analysisr calcd. for C H F O 5 C, 46.00; H, 5.79; F, 12.1. Found: C, 46.09;'H, 5.88; F, 12.0, 12.3.

Triethyl 4,4-difluoroaconitateis made by dehydrating I .triethyl 2,2-difiuorocitrate, as by heating With phosphorus After recrystallization from ether-benzene in 84% return The ester is hydrolyzed by refluxing 224. parts with 1000 parts of 10% hydrochloric acid r'o r one hour and then evaporating under vacuum, The crystalline prodnet is washed with trifluoroacetic acid to give l51'parts' (81% of theory) of u,a-difluorooxa'lacetic acid hydrate. .It melts at 116-118 C; after recrystallization from tri- Example Il. 3,3-diflu or o'malic acid (ma-d ifliioromalic 7 acid) I W A mixture of parts of" tate, 53 parts of ether and 0.5 part of ruthenium dioxide catalyst ishydrogenated at 75-80" C. and1000-2000 lb./sq.' in. hydrogen pressure. 7

The product i s- 'filtered and distilled to giye;25. parts (74% of theory) of diethyl 3,3-difluoromalate, B. P. 694 70" C./0.5 mm., n 1.4078.

D et m-difl q te s also re t ethyl 3,3-clifluoromalate by adding itto sodiumhereby.- dride in pyridine at 20-25 C. i

Analysis.Calcd. rore fl n o c, 42.47; H, 5.85; F, 16.80. Found: c, 42.30;; 5.48; F, 16.8, 16.9..

The ester is hydrolyzedto 3,3 d ifluo1'omalic acid (n w, dlfluoromalic acid) by refluxing 22 parts with 50parts of 10% hydrochloric acid for three hours; Evaporation of the solution and recrystallization of the 3,3-difluoromah cid g s p t of t eqr M- 1 Analysisr-Calcdf 'F, 22.3. Found: c, 28.66;'H, 2163;F, 21.

Example .111 7 bath. A portion of a mixture of 112 parts of diethyl q,a-difluorooxalacetate, 84 parts of ethyLbroinoacetate i 1 pentoxide.

7 Alternatively tri'ethyl 2,2-difluor ocitrate is treated with phosphorus pentabromide to replace the hydroxyl group with bromine and the product is heated with aqueous sodium hydroxide to obtain sodium'4,4- difluoroaconitate. By acidifying a solution ofthe salt with sulfuric acid. and extracting with ether, the free 4,4difiuo roaconitic' acid is obtained.

PART B.DIETHYL 2,2-DIFLUOROCITRATE (DI- ETHYL u,ir-DIFLUOROCITRATE) V To a mixture of 3.2 parts of malonic 'acid and 7' parts of pyridine is slowlyadded 6.7 parts of diethyl a,a-di-.

fiuorooxalacetate. The mixture is then acidified with dilute sulfuric acid and extracted with ether; Evaporation. of the etherleaves 7.8 g. (92% yield) of diethyl it, melts at 113-114 C.

for .C1QH14F2O7I C, H, a F, 13.4. Found: C, 41.86; H, 5.13; F, 13.1.

PART C.2,2-DIFLUOROCITRIC ACID giouonrnnarn (u,a-DIELUQBOCITRIC AC i V Diethyl difluorocitrate 31.2 parts) is dissolved in 75 parts of water containing 132 parts of sodiumhydroxide and allowed to stand 65 hours at"25 C. Hydrochloric acid (d. 1.18; 35 parts) is then added and the solution Theether is dried over magis extracted with ether.

; nesium sulfate and evaporated to give 23 parts Ofsyrupy difluorocitric acid. This is allowed to stand until crysdiethyl a,a-difluorooxalace- LO- 1 'BUTANE FROM VINYLIDENE CHLORIDE AND HLO-.

talline and recrystallizedfroina mixture of ether and benzene- 'The compound is the monohydrate .o f 2',2- difluorocitric acid which melts at 89-90 C. Analylsis.Calcd. for C H F O :H O:

3.28; F, 15.44. Found: C, 29.38; H, 3.49; F, 15.44.

STEP1r-1,1.2 TRICHLORO 2,3,3 TRIFLUOROCZI;

BOTR'IFLUOROETHYLENE A staiuless steel bomb is charged with 350 parts of.

vinyli djene chloride, 1 part of hydroquinone. and 300 parts of chlorotriiiucroethylene. 1The mixture is heated for 10 hours atl C. under autogenous pressure; The product is filtered from polymer and then distilled to give 266. parts (48% yield) of 1,1,2-trichloro-2,3',3-tri-.

fluorocyclobutane boiling at' -121 C., r1 1.4139. Analysis.+Calcd. for 'C H' Cl F C, 22:51; 'H',;0.95;-

c1,49.8s.-. Found: c, 22.61; H, 1.09; (:1, 49.32;

STEP'2 ..1 onnono- 2,3,3 rmnruonocrcnonurnun. FROM 1,1,2 'rnrcrnono '2,s, 8- TRVIFLUOROCYCLOU BUTANE 'Inta glass-reaction 'vesselfitted'witlr anefiicientirefiux condenser, ,sealed stirrer :and addition, funnel are placed parts:of.9.5.% zinc dust and 243 'parts'ot absolute ethanol; :The.;alcohol is refluxedand400 parts of 1,1;29 tricljiloroi2,3,3rtrifluorocyclobutanei is. slowly added.. The 1 mixture; is rcfluxediforxtwo. hours after theendzof the addition. 'Thegmixtureisf'cooled.and :1 500;parts' of water containing25fparts oi hydrochloric. acid isadded; :The'

5 and distilled. The yield of 1-chloro 2,3,3-trifluorocyclobutene is 177 parts (66%), B. P. 51.5-52 C. n 1.3614. Analysis.-Calcd. for C H ClF Cl, 24.88. Found: Cl, 24.50.

STEP 3.-2,2-DIFLUOROSUCCINIC ACID FROM l-CHLO- RO-2,3,3-TBIFLUOROCYCLOBUTENE In a glass reaction vessel fitted with stirrer, thermometer, addition funnel, and ice-salt bath are placed 4000 parts of water, 160 parts of sodium hydroxide and 316 parts of potassium permanganate. 1- chloro-2,3,3-trifluorocyclobutene (214 parts) is added slowly at 1520 C. The reaction is complete in three hours. The manganese dioxide is filtered 01f, washed with water, and the filtrate is reduced in volume on a steam bath. After addition of 312 parts of sulfuric acid, the filtrate is extracted with ether. After the ether solution has been dried with magnesium sulfate it is evaporated to give 182 parts (79% yield) of 2,2-difluorosuccinic acid. The product is recrystallized from acetone-benzene in 88% return (2 crops) and melts at 144-145 C.

Analysis.Ca1cd. for C H F O C, 31.17; H, 2.62; F, 24.66. Found: C, 30.90; H, 2.80; F, 24.68.

This acid is stable in water in contrast to a,B-difluorosuccinic acid which decomposes to acetylenedicarboxylic acid on contact with water.

2,2-difluorosuccinic acid is converted to its diethyl ester as follows:

One hundred parts of 2,2-difluorosuccinic acid, 243 parts of absolute ethanol, and 18 parts of sulfuric acid are refluxed for two hours. The alcohol is boiled E, and 243 parts more of ethanol and 9 parts of sulfuric acid are added. Refluxing is continued for 16 hours, and the alcohol is again boiled oil. The product is poured into water, and the organic layer is washed with sodium bicarbonate solution followed by water. After drying over magnesium sulfate and distillation, 109 parts (81% yield) of diethyl 2,2-difluorosuccinate is obtained, B. P. 53-55 C./1 mm., 205207 C./749 mm., 11 1.3912.

Analysis.Calcd. for C H F O C, 45.71; H, 5.76; F, 18.08. Found: C, 46.10; H, 5.86; F, 18.54.

Example V.Dimethyl 4,4 difluoro 2 oxoglutarate (dimethyl a,nt-difluoro-gamma-oxoglumrate) STEP 1.l\IETHYL 2 CHLORO 2,3,3 TRIFLUORO- CYCLOBUTANECARBOXYLATE FROM METHYL ACRY- LATE AND CHLOROTRIFLUOROETHYLENE A stainless steel bomb is charged with 300 parts of methyl acrylate, 1 part of hydroquinone, and 300 parts of chlorotrifluoroethylene. The mixture is heated at 180 C. for hours. Distillation of the product gives 383 parts of methyl 2 chloro 2,3,3-trifluorocyclobutanecarboxylate boiling at 163-165 C., n 1.3952. The yield Analysis.Calcd. for C H ClF O Cl, 17.50. Found:

STEP 2.METHYL 2,3 3-TRIFLUOR0-1-CYCLOBUTENE-L CARBOXYLATE FROM MErHYL 2-CHLOR0-2,3,3-TRI- FLUOROCYCLOBUTANECARBOXYLATE In a glass reaction vessel fitted with stirrer, reflux condenser, and addition funnel are placed 303 parts of methyl 2 chloro 2,3,3 trifluorocyclobutanecarboxylate and 350 parts of ether. One hundred sixty parts of triethylamine is added and the mixture is refluxed for one-half hour. Water (800 parts) is added and the ether layer is washed with 10% hydrochloric acid and water. After the ether solution is dried over magnesium sulfate, it is distilled to give 195 parts (79% yield) of methyl 2,3,3- trifluoro-1-cyclobutene l-carboxylate, B. P. 128-129 C. n 1.3850.

Analysis.-Calcd. for C l-1 1 0 C, 43.38; H, 3.03; F, 34.32. Found: C, 43.16, 43.20; H, 3.31, 3.42; F, 34.28.

STEP 3.METHYL 3,3-DIFLUORO-2-METHOXY-1-CYCLO- BUTENE-l-CARBOXYLATE FROM METHYL 2,3,3-TRI- FLUORO-l-CYCLOBUTENE-LCARBOXYLATE A glass reaction vessel is fitted with stirrer, reflux condenser, device to add powder, and ice bath. In the vessel are placed 178 parts of methyl 2,3,3 tritluoro 1 cyclobutene-l-carboxylate and 350 parts of anhydrous ether. Fifty-eight parts of solid sodium methylate is then added in portions. After all is added, the ice bath is removed and the mixture is stirred for one hour. The sodium fluoride is filtered off and rinsed with ether. The filtrate is distilled to give 114 parts (64% yield) of methyl 3,3-

difluoro-Z methoxy l-cyclobuetene-l-carboxylate, B. P.

Analysis.-Calcd. for C H F O C, 47.21; H, 4.53; F,

21.34. Found: C, 47.49; H, 4.59; F, 21.48.

STEP 4.-DIMETHYL 4,4-DIFLUORO-2-OXOGLUTARATE FROM METHYL 3,3-DIELUORO-2-METHOXY-1-CYCLO- BUTENE-l-CARBOXYLATE A solution of 25 parts of methyl 3,3-difluoro-2-methoxyl-cyclobutene-l-carboxylate in 130 parts of methylene chloride is cooled in a Dry Ice/ acetone mixture and ozone is passed in until the blue color of ozone becomes evident.

For decomposing the rather stable ozonide a simple still is arranged with a still pot in an oil bath maintained at 200 C. and an addition funnel in the still head. The ozonized solution is added slowly. Material collected in the receiver of the still is heated on a steam bath to evaporate methylene chloride and then returned to the still, after which all of it remains in the still pot. The product is distilled at 1 mm. in a simple still to get rid of considerable tar and then fractionated to give'dimethyl 4,4-difluoro-Z-oxoglutarate, B. P. 8991 C./ 3 mm., n 1.4064.

Analysis.Calcd. for G T-1 F 0 C, 40.0; H, 3.84; F, 18.1. Found: C, 39.2; H, 4.01; F, 18.7.

The ozonide may also be decomposed by dissolving it in 98% acetic acid and carefully adding zinc dust. This gives a product, B. P. 86-88 C./1 mm., n 1.4140, in 46% yield which is a mixture of dimethyl 4,4-difluoro 2-oxoglutarate and dimethyl 4,4-difluoro-2-hydroxyglutarate.

Analysis.-Found: C, 40.1; H, 4.85; F, 17.7.

The reduced form can be reoxidized to the keto form by the action of a mild oxidizing agent, such as N-bromosuccinimide.

4,4-difiuoro-2-oxoglutaric acid is obtained from the ester by shaking with four parts of concentrated hydrochloric acid for 24 hours and removal of the hydrochloric acid under vacuum.

Trimethyl a,a-difluorooxalosuccinate and trimethyl 01,0:- difluoroisocitrate are prepared by the following reactions:

CHzO O C GH=CH-CH=CHG O O CH:

C F Cl-C F2 CHsO 0-0 F:

CHaOOCCOHO OOCH:

' OH CFCl-(F F2 CHsOOCCH-CHCOOH 6 CHaOOCCH-CHCOOCH3 .ether.

,2 JTRIYFLUOROCYCLOVBU'QYD)ACRYLATE' p l ljimethyl muconate- 113-2 pa'rt's), 261 parts of benz'enegf oa s-par: of hydroquinone and 188 parts of-chlorotrifluoroethylene are heated in aclosed reactor for. 8 hours at 190 C; The beniene is boiled off and the product isQdistilled Ar za lysis. Calc d.for; c H c1F o.;c, 41f90; 11,3,52;

01,1237. Found: c, 41.84; H, 3.4201, 12.05.;

smr- 2. DIMETHYL,a-cnLo110-3,4,4-TRIFLUoRocYcLo -BUTANE-l,2-DICARB0XYLATE 'io a'stiired. mixture of 138 parts of potassium per-L manganate, 16 parts of acetic acid and 800 parts of water maintained at'15'20 C. is slowly added 69 parts of -methyl 3-(4-carbomethoxy 3-chloro 2,2,3-trifiuorocycloej butyl)a crylate.. The mixture is stirred one hour at the endand sulfur dioxide is then passed in with cooling until the 'mangahese dioxidedisappears. Hydrochloric acid (284 parts) is added and' the solution is extractedwitli The ether solution is dried .withmagneslium S1111 fate and evaporated-to give the monoester ofthe desired product. The monoester. is esterified' by refluxiug'with ll8 parts-of methanol and 7 parts of sulfuric acid for hours. The methanol is thenidistill'ed ofi, the ester is washedwith water, dried, and distilled; yield, 26 partsis 'in adeerirwith the structure. a

nuclear. magnetic resonance spectrum of the compound Q1, 13.61; auna; .C, 37. 48;1H, 3.53; Cl, 13.90; p

2,3-DICABBOXYLATE "i ro; a. wa r 26 A parts of dimethyl" scum-3,4,4.

trifluorocyfclobutaned,2 dicarboxylate in 107 parts of ether is added 11 parts of triethylamine. Triethylamine 1 hydrochloride immediately precipitates; After one-half l hour this is filtered ofi. The ether solution is washed with 5% hydrochloric acid to remove excess triethylarnine,

. then washed. with water; dried and distilled. ,The yield -Q diuiethyl 1,4,4-trifluorocyclobutene-2,3-dicarboxylate 7 i519 parts(88%) 'Bl' P. 49-51 C./l.5 111111., 71 1.4052.

' under-vacuum; The crude product is thenfractiona'ted". a through acolumn ito' give'47' parts 21%; yield) Of methyl sucinic" acid by shakingi forl lfldaysat O-Z-S'T'QI-With V parts of. hydrochloricacid (.d'. 1.18). Mild conditions" areuse'd because of the easeordecarboxylation ofthe free acid. 1

l Trimethyl oot-difiuoroisocitrate prepared the hy- V drogenation of trimethyl b a-difluorooxalosuccinate or'the oz'on'ide of dimethyl 1-methoxy 4,4-difluorocyclobutene' 2,3-dicarboxylat'e "in methanol'or ether at'40 C. in i the presence of ruthenium" dioxide catalyst. V a

I .'.The free acid is prepared by refluxing,the esterfor three hours with 10% hydrochloricacid and extracting the a,a-difiuoroisocitric acid with ether.

' react with excess manganous carbonate, the excess is Theflnuclearflmagnetic resonance spectrum agrees with the structure. I i

V UTENE-2,3-DIGABBOXYLAT V v V ln' afclosed. rea'eti'on vessel fitted with thermometer,

' stirrerahd de ic'e for adding powder are placed 14.5 parts of dirn'ethyl': 'l ,4,4 trifiuorocyclobutene-Z,3-dicarbdxylate ahd 7lpa rt sf of ether. Sodium methylate'powder (3.8

' f p rs-yrs gradually added'while the solution is keptbelow l5 C; .The mixture is stirred for 1 hour, the sodiurn' fluoridejis thenfiltered off, and the filtrate is distilled.

Theyield of dimethyl l-methoxy-4,4-difluorocyclobutene- 2,3 dicarboxylate is 'l-1'.7 parts (77%), B. P. 75-77 'C./4 mm., n 1.4378. The nuclear magnetic resonance spectrum agrees with the structure. -11.

'Dimethyl 1-ruethoxy 4,4-difiuorocyclobutene-2,3-dicarboxylateis dissolved in 5 parts of methylene chloride and .ozone' is passed in et 75 C .Theozonide' isdeeomp'osed by reflu xing for 15 hours ,in methanolcontaining 2%'. of sulfuric 'acid. The" methanol is distilled off, the

product is washed 'wit'h wateqdried andldistilled.

The ester is hydrolyzed to the free a,o -difluoro-fi-oxalofiltered. OE, and the soluble manganese salt is allowed to crystallize out by evaporation of ,the water. -r ecopper, barium, zinc, iron, magnesium, mercury and V V lead'salts are readily prepared in this way. The ammonium salts'are prepared by treating an aqueous ,'solu-.

tion of thedifluoro acid with ammonia until neutral'and f;

evaporating the solution. h 1

f Ester are prepared by refluxing a mixture ofthe di fluo'ro acid and arl alcohol, i. e., analk'anol, particularly:

of 1-to8 orniore carbon'atoms'such as methanohethanol,

butanol, octanol andthe' like, in the preserme -of a trace Y a i of mineral acidLThe esters of these difluoro'acidgfsuch; e as the alkyl esters arethus readily preparedl- ,A'rnides and "Nesubstitut'ed amides nrthese difl dro-l substituted acids, such as the alkyl and dialkyl-N-substiy 7 t ut'ed'amides,particularly wherein the alkyl' groupsare of 1 to 8 or'more carbon'atorns; are'obtained by-passii1'gl ammonia of'a primary or secondary amine,; such as an' 7 alkylamine or dialkylamine, i. e-., 'methylamine, dim'e thyl-I 5 'amine, octylamine, or dioctylamine and the like, into 7 I V estersor acidchlorides of; theidifluoro acids. I Thug-magi} difluorooxalaeetamide'and the amides of these difluoro g acids as well-as theTN-methyl,N-diinethyl, iN-octyh'N dioctyl, and other'N-substitutedamides of these. difluoro V ,1 E

acids are readily prepared; For example, difluorooxal V 'acetarnide is prepared by -mixing diethyl "difluorooxa alacetate with aqueous ammonia,-acidifying the 'solution,;

ahd extracting'the amidefwith a-wat'erdmmiscibh solvent. These 'a,u-difluoro derivatives of the aci ds;-inthe-. 'tri- 'carboxylic acid cycle are useful as fungicides, as illus tratedby their strong inhibitionrof tomato early-blight" (A'lternaria sblani). These neon-difluoro acids areal'so use- 1 ful as insecticides'and miticides as"illustrated-by "their toxicity to milk'weed bugs, alphids and' twoas'potted mites. A'2 aqueous solution of fifi-difiuorooxalacetic acid hydrate' spray ed on milkweed ibugsicauses a %",killQ The. preventive f ungitoxic' activity of "diethyl-exudifluorooxalacetate is illustrated by the ,resultsof greenhouse'tests with tomatoplar1ts asdescribed iby. McCalla'n' and Welliuan (Crop Protection Digest, Bulletin 68,.Iuly. .1943, pages 94l34). In such a test one set of "tomato plants i'sYsprayed with a Q.0016 aqueous solution of.

1 diethyl a,a-difiuorooxalacetate and ariother set' is sprayed f With'a' 0.2% aqueous solution-of diethyl a,'a-difluoro-' oxalacetate. The treated plants,'-,along withga corresponding set of untreated controls, are inoculated with .toinato early blight (Alternaria solani); Lesion counts are made; after three days. 'The control plants show %fdisease, C r the plants'treated with-0.0016% diethyl a,d-,difluorooxalacetate show 9% disease, and the plants sprayed with 0.2% diethyl a,ot-difiuorooxalacetate'show no disease; 7

The approximate LD of diethyl. agd-difiuorooxal acetate for laboratory white mice (intraperitoneal route) is 50-75 mg./kg. of body weight.

In the test against tomato early blight as described above, plants sprayed with a 0.2% aqueous solution of 3,3-difluoromalic acid show 4% disease compared to 100% for controls. The approximate LD of 3,3-difiuoromalic acid for laboratory white mice (intraperitoneal route) is 50-75 mg./kg.

In the test against tomato early blight as described above, plants sprayed with 0.2% triethyl 2,2-difluorocitrate in 90:10 acetonezwa ter show 4% disease compared to 100% disease for the controls.

In the test against tomato early blight, plants sprayed with a 0.2% aqueous solution of 2,2-difluorosuccinic acid show 6% disease compared to 100% for controls. A 2% solution sprayed on aphids causes a 90% kill and on two-spotted mites produces a 100% kill. The approximate LD of 2,2-difluorsuccinic acid for laboratory white mice (intraperitoneal route) is 100-150 mg./kg.

Furthermore, the insecticidal and miticidal activity of these new compounds is surprisingly greater than that of known compounds which are related in structure. For example, 0:,a-difiHOIOSUCClI1iC acid is several fold more effective in these respects than tetrafluorosuccinic acid or a,u-difluoroglutaric acid as shown in the following table:

Tetrafluorosuccinic Acid a, a-Dlfilloroglutaric Acid Aphids Mites As many apparently widely difierent embodiments of this invention may be made without departing from the spirit and scope thereof, it is to be understood that this invention is not limited to the specific embodiments thereof except as defined in the appended claims.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

l. A fluorine-containing compound selected from the class consisting of acids of the tricarboxylic acid cycle having a methylene carbon atom alpha to a carboxyl group and having directly attached to this methylene carbon atom two fluorine atoms, their metal and ammonium salts, their alkyl esters wherein the alkyl group contains 1 to 8 carbon atoms, their amides and their N-alkyl and N-dialkyl substituted amides wherein the alkyl groups contain 1 t0 8 carbon atoms.

2. An acid of the tricarboxylic acid cycle having a methylene carbon atom alpha to a carboxyl group and having directly attached to this methylene carbon atom two fluorine atoms.

3. An alkyl ester of an acid of the tricarboxylic acid cycle having a methylene carbon atom alpha to a carboxyl group and having directly attached to this methylene carbon atom two fluorine atoms, said alkyl group containing 1 to 8 carbon atoms.

. Diethyl u,a-difluorooxalacetate. Diethyl a,a-difluorocitrate.

. a,a-Difluorocitric acid.

. a,a-Difluorosuccinic acid.

References Cited in the file of this patent UNITED STATES PATENTS Kharasch Aug. 26, 1947 OTHER REFERENCES 

1. A FLUORINE-CONTAINING COMPOUND SELECTED FROM THE CLASS CONSISTING OF ACIDS OF THE TRICARBOXYLIC ACID CYCLE HAVING A METHYLENE CARBON ATOM ALPHA TO A CARBOXYL GROUP AND HAVING DIRECTLY ATTACHED TO THIS METHYLENE CARBON ATOM TWO FLUORINE ATOMS, THEIR METAL AND AM MONIUM SALTS, THEIR ALKYL ESTERS WHEREIN THE ALKYL GROUP CONTAINS 1 TO 8 CARBON ATOMS, THEIR AMIDES AND THEIR N-ALKYL AND N-DIALKYL SUBSTITUTED AMIDES WHEREIN THE ALKYL GROUPS CONTAIN 1 TO 8 CARBON ATOMS. 